Elisa Zhang

All Publications

• Uterine injury during diestrus leads to embryo spacing defects and perturbations in the COX pathway in subsequent pregnancies Zhang, E. T., Wells, K. L., Steinmetz, L. M., Baker, J. C. bioRXiv. 2022

  Abstract

  Uterine injury from procedures such as Cesarean sections (C-sections) often have severe consequences on subsequent pregnancy outcomes, leading to disorders such as placenta previa, placenta accreta, and infertility. With rates of C-section at approximately 30% of deliveries in the US and that are projected to continue to climb, a deeper understanding of the mechanisms by which these pregnancy disorders arise and opportunities for intervention are needed. However, there are no animal models to date that comprehensively assess the consequences of uterine injury. Here we describe a rodent model of uterine injury on subsequent in utero outcomes. We observed three distinct phenotypes: increased rates of resorption and death, embryo spacing defects, and placenta accreta-like features of reduced decidua and expansion of invasive trophoblasts. We show that the appearance of embryo spacing defects depends entirely on the phase of estrous cycle at the time of injury. Using RNA-seq, we identified perturbations in the expression of components of the COX/prostaglandin pathway after recovery from injury, a pathway that has previously been demonstrated to play an important role in embryo spacing. Therefore, we demonstrate that uterine damage in this mouse model causes morphological and molecular changes, most notably perturbed expression of COX/prostaglandin pathway-related genes, that ultimately lead to placental and embryonic developmental defects.

• PRG2 and AQPEP are misexpressed in fetal membranes in placenta previa and percreta1. Biology of reproduction Zhang, E. T., Hannibal, R. L., Badillo Rivera, K. M., Song, J. H., McGowan, K., Zhu, X., Meinhardt, G., Knofler, M., Pollheimer, J., Urban, A. E., Folkins, A. K., Lyell, D. J., Baker, J. C. 2021

  Abstract

  The obstetrical conditions placenta accreta spectrum (PAS) and placenta previa are a significant source of pregnancy-associated morbidity and mortality, yet the specific molecular and cellular underpinnings of these conditions are not known. In this study, we identified misregulated gene expression patterns in tissues from placenta previa and percreta (the most extreme form of PAS) compared with control cases. By comparing this gene set with existing placental single-cell and bulk RNA-Seq datasets, we show that the upregulated genes predominantly mark extravillous trophoblasts. We performed immunofluorescence on several candidate molecules and found that PRG2 and AQPEP protein levels are upregulated in both the fetal membranes and the placental disk in both conditions. While this increased AQPEP expression remains restricted to trophoblasts, PRG2 is mislocalized and is found throughout the fetal membranes. Using a larger patient cohort with a diverse set of gestationally aged-matched controls, we validated PRG2 as a marker for both previa and PAS and AQPEP as a marker for only previa in the fetal membranes. Our findings suggest that the extraembryonic tissues surrounding the conceptus, including both the fetal membranes and the placental disk, harbor a signature of previa and PAS that is characteristic of EVTs and that may reflect increased trophoblast invasiveness.

  View details for DOI 10.1093/biolre/ioab068

  View details for PubMedID 33982062

• Architecture of the human XPC DNA repair and Stem Cell Coactivator Complex PNAS Zhang, E. T., He, Y., Grob, P., Fong, Y. W., Nogales, E., Tjian, R. 2015; 112 (48): 14817–14822

  View details for DOI 10.1073/pnas.1520104112

• Functional and mechanistic studies of XPC DNA-repair complex as transcriptional coactivator in embryonic stem cells PNAS Cattoglio, C., Zhang, E. T., Grubisic, I., Chiba, K., Fong, Y. W., Tjian, R. 2015: E2317–E2326

  View details for DOI 10.1073/pnas.1505569112

• Structural basis of histone H2A-H2B recognition by the essential chaperone FACT NATURE Hondele, M., Stuwe, T., Hassler, M., Halbach, F., Bowman, A., Zhang, E. T., Nijmeijer, B., Kotthoff, C., Rybin, V., Amlacher, S., Hurt, E., Ladurner, A. G. 2013; 499 (7456): 111-?

  Abstract

  Facilitates chromatin transcription (FACT) is a conserved histone chaperone that reorganizes nucleosomes and ensures chromatin integrity during DNA transcription, replication and repair. Key to the broad functions of FACT is its recognition of histones H2A-H2B (ref. 2). However, the structural basis for how histones H2A-H2B are recognized and how this integrates with the other functions of FACT, including the recognition of histones H3-H4 and other nuclear factors, is unknown. Here we reveal the crystal structure of the evolutionarily conserved FACT chaperone domain Spt16M from Chaetomium thermophilum, in complex with the H2A-H2B heterodimer. A novel 'U-turn' motif scaffolded onto a Rtt106-like module embraces the α1 helix of H2B. Biochemical and in vivo assays validate the structure and dissect the contribution of histone tails and H3-H4 towards Spt16M binding. Furthermore, we report the structure of the FACT heterodimerization domain that connects FACT to replicative polymerases. Our results show that Spt16M makes several interactions with histones, which we suggest allow the module to invade the nucleosome gradually and block the strongest interaction of H2B with DNA. FACT would thus enhance 'nucleosome breathing' by re-organizing the first 30 base pairs of nucleosomal histone-DNA contacts. Our snapshot of the engagement of the chaperone with H2A-H2B and the structures of all globular FACT domains enable the high-resolution analysis of the vital chaperoning functions of FACT, shedding light on how the complex promotes the activity of enzymes that require nucleosome reorganization.

  View details for DOI 10.1038/nature12242

  View details for Web of Science ID 000321285600044

  View details for PubMedID 23698368

• Clotting factor genes are associated with preeclampsia in high-altitude pregnant women in the Peruvian Andes. American journal of human genetics Nieves-Colon, M. A., Badillo Rivera, K. M., Sandoval, K., Villanueva Davalos, V., Enriquez Lencinas, L. E., Mendoza-Revilla, J., Adhikari, K., Gonzalez-Buenfil, R., Chen, J. W., Zhang, E. T., Sockell, A., Ortiz-Tello, P., Hurtado, G. M., Condori Salas, R., Cebrecos, R., Manzaneda Choque, J. C., Manzaneda Choque, F. P., Yabar Pilco, G. P., Rawls, E., Eng, C., Huntsman, S., Burchard, E., Ruiz-Linares, A., Gonzalez-Jose, R., Bedoya, G., Rothhammer, F., Bortolini, M. C., Poletti, G., Gallo, C., Bustamante, C. D., Baker, J. C., Gignoux, C. R., Wojcik, G. L., Moreno-Estrada, A. 2022

  Abstract

  Preeclampsia is a multi-organ complication of pregnancy characterized by sudden hypertension and proteinuria that is among the leading causes of preterm delivery and maternal morbidity and mortality worldwide. The heterogeneity of preeclampsia poses a challenge for understanding its etiology and molecular basis. Intriguingly, risk for the condition increases in high-altitude regions such as the Peruvian Andes. To investigate the genetic basis of preeclampsia in a population living at high altitude, we characterized genome-wide variation in a cohort of preeclamptic and healthy Andean families (n= 883) from Puno, Peru, a city located above 3,800 meters of altitude. Our study collected genomic DNA and medical records from case-control trios and duos in local hospital settings. We generated genotype data for 439,314 SNPs, determined global ancestry patterns, and mapped associations between genetic variants and preeclampsia phenotypes. A transmission disequilibrium test (TDT) revealed variants near genes of biological importance for placental and blood vessel function. The top candidate region was found on chromosome 13 of the fetal genome and contains clotting factor genes PROZ, F7, and F10. These findings provide supporting evidence that common genetic variants within coagulation genes play an important role in preeclampsia. A selection scan revealed a potential adaptive signal around the ADAM12 locus on chromosome 10, implicated in pregnancy disorders. Our discovery of an association in a functional pathway relevant to pregnancy physiology in an understudied population of Native American origin demonstrates the increased power of family-based study design and underscores the importance of conducting genetic research in diverse populations.

  View details for DOI 10.1016/j.ajhg.2022.04.014

  View details for PubMedID 35588731

• Molecular and Cellular Characterization of Placenta Previa and Accreta. Zhang, E. T., Rivera, K., Hannibal, R. L., McGowan, K., Zhu, X., Meinhardt, G., Knoefler, M., Pollheimer, J., Folkins, A., Lyell, D. J., Baker, J. C. SAGE PUBLICATIONS INC. 2019: 262A–263A

  View details for Web of Science ID 000459610400590

• Dynamics of CRISPR-Cas9 Genome Interrogation in Living Cells Science Knight, S. C., Xie, L., Deng, W., Guglielmi, B., Witkowsky, L. B., Bosanac, L., Zhang, E. T., El Beheiry, M., Masson, J., Dahan, M., Liu, Z., Doudna, J., Tjian, R. 2015; 350 (6262): 823-826

  View details for DOI 10.1126/science.aac6572

• Exposure to solar UV-B radiation accelerates mass and lignin loss of Larrea tridentata in the Sonoran Desert Plant Ecology Day, T. A., Zhang, E. T., Ruhland, C. T. 2007; 193 (2): 185-194
• A C-terminal motif targets Hedgehog to axons, coordinating assembly of the Drosophila eye and brain Dev Cell Chu, T., Chiu, M., Zhang, E., Kunes, S. 2006: 635–646

  View details for DOI 10.1016/j.devcel.2006.03.003